"Broke Through Solid Tumor Barriers"... Korean Researchers Achieve First Quantitative Analysis of CAR-NK Cell Infiltration [Reading Science]

Three-Dimensional Analysis of Immune Cell Migration Deep into Pancreatic Tumor Tissue

"Measuring Extravasation May Become a New Evaluation Standard for Immune Cell Therapies"

A domestic research team has, for the first time, succeeded in quantitatively analyzing in three dimensions how deeply CAR-NK cells—a next-generation immune cell therapy—can infiltrate solid tumor tissues. This study precisely demonstrates why CAR-NK cells, which have shown strong efficacy against blood cancers, are less effective against solid tumors such as pancreatic cancer. Experts consider this research a potential new benchmark for evaluating the performance of immune cell therapies targeting solid tumors.

The research teams led by Song Junmyung at the College of Pharmacy, Seoul National University, and Cho Deok at the School of Medicine, Sungkyunkwan University, announced that they quantitatively analyzed the extravasation and tumor infiltration of CAR-NK cells using a three-dimensional imaging technology based on tumor clearing. The results of their research were published on April 23 in the international journal Theranostics.

A schematic diagram showing the migration process of CAR-NK cells penetrating into solid tumors. CAR-NK cells exit the blood vessels, infiltrate deep into the tumor tissue, and attack pancreatic cancer cells. However, the dense extracellular matrix and high pressure of the tumor microenvironment act as barriers that hinder immune cell infiltration. Provided by the research team

CAR-NK cells are natural killer (NK) cells that have been genetically engineered to recognize cancer cells. While they demonstrate high anti-cancer efficacy in blood cancers, their effectiveness is limited in solid tumors such as pancreatic cancer due to the dense extracellular matrix, abnormal blood vessels, and immunosuppressive tumor microenvironment, which hinder their entry into the tumor interior. In particular, the 'extravasation' process, in which immune cells exit blood vessels and migrate into tumor tissues, has been identified as a critical step in determining therapeutic outcomes. However, few studies have quantitatively analyzed this process at the microscopic level.

The research team developed MSLN-targeted CAR-NK-92 cells and CAR-IL-15-NK-92 cells that co-secrete interleukin-15 (IL-15), and intravenously injected them into mouse models with transplanted pancreatic cancer (PANC-1). They then applied a CLARITY-based imaging technique to clear the tumor tissues and, while preserving the vascular structure, analyzed the migration paths of the immune cells in three dimensions.

Experimental results showed that CAR-NK cells infiltrated much more extensively and deeply into the tumor tissue compared to conventional NK cells. The extravasation rate for standard NK-92 cells was 57.4%, whereas MSLN-CAR-NK-92 cells achieved 85.3%. The number of cells that exited the blood vessels increased more than threefold, from 2,311 to 7,717. The maximum penetration depth also increased from approximately 73 micrometers for standard NK cells to about 174 micrometers for CAR-NK cells.

Notably, CAR-NK cells secreting IL-15 greatly expanded the area of tumor cell death. The researchers explained that the CAR design not only enhanced the cancer cell recognition capability but also improved both the motility and anti-cancer efficacy within actual solid tumor tissues.

"A New Benchmark for Evaluating the Performance of Solid Tumor Immunotherapy"

The research team highlighted the 'extravasation efficiency' as a core finding of this study. Until now, much research had focused on the cytotoxicity of CAR-NK cells themselves, but there has been a lack of quantitative standards for how well these cells actually infiltrate tumors.

The research team stated, "Extravasation efficiency could become an important indicator for evaluating the performance of targeted immune cell therapies for solid tumors in the future," adding, "This platform is applicable not only to pancreatic cancer but also to a variety of solid tumor models, such as cholangiocarcinoma."

This content was produced with the assistance of AI translation services.